Osteosarcoma is the most common primary bone cancer in children and adolescents. In spite of aggressive treatment, osteosarcoma has a high mortality rate with minimal improvements in survival over past few decades. Polyphyllin I (PPI), a component in the traditional Chinese medicinal herb Paris polyphylla Smith, has been shown to have anti-tumor properties. However, its mechanism as an anti-osteosarcoma agent has not been well elucidated. In this study, we found that PPI suppressed osteosarcoma cell viability, arrested cell cycle in G2/M phase, induced apoptosis and inhibited invasion and migration of osteosarcoma cells. Moreover, PPI significantly suppressed intratibial primary tumor growth in xenograft orthotopic mouse model without any obvious side effects. These therapeutic efficacies were associated with inactivation of Wnt/β-catenin pathway, as PPI treatment decreased the amount of p-GSK-3β, leading to down-regulated levels of active β-catenin. PPI induced inhibition of osteosarcoma cell viability was abolished upon addition of GSK-3β specific inhibitor, CHIR99021, while PPI induced inhibition of osteosarcoma cell viability and migration were potentiated by β-catenin silencing. These findings suggested that, in vitro and in vivo, PPI treatment inhibited osteosarcoma, at least in part, via the inactivation of Wnt/β-catenin pathway. Thus, PPI could serve a novel therapeutic option for osteosarcoma patients.
Prostate cancer is the second most commonly diagnosed malignancy and the sixth global primary cause of malignancy-associated fatality. Increased invasiveness and motility in prostate cancer cells are associated with ubiquitin proteasome system-regulated epithelial to mesenchymal transition (EMT). Impairment of the endoplasmic reticulum (ER) causes ER stress due to the accumulation of unfolded proteins and altered cell survival. In the current study, the effect and mechanism of matrine on cell apoptosis, viability, migration and invasion of human prostate cancer cells in vivo and in vitro through the unfolded protein response (UPR)/ER stress pathway were investigated. Matrine inhibited proteasomal chymotrypsin-like (CT-like) activity in the prostate carcinoma cellular proteasome. Upregulated vimentin and N-cadherin and downregulated E-cadherin were also observed in vitro and in vivo. In vitro analyses showed that matrine repressed cell motility, viability and invasion, arrested the cell cycle at the G0/G1 phase and induced prostate cancer cell apoptosis. Furthermore, matrine activated the UPR/ER stress signaling cascade in prostate cancer cells and tumor tissues of xenograft-bearing nude mice. Results also demonstrated that the anti-apoptotic protein Bcl-2 was downregulated, the pro-apoptotic protein Bak was upregulated and the cell growth and cell cycle-related proteins c-Myc, Cyclin B1, Cyclin D1 and CDK1 were downregulated. Moreover, matrine inhibited tumor growth and Ki-67 expression in xenograft-bearing nude mice. To the best of our knowledge, the present study indicated for the first time that matrine exerted marked anticancer functions in human prostate carcinoma in vivo and in vitro through activation of the proteasomal CT-like activity inhibition mediated by the UPR/ER stress signaling pathway.
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